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CTCF ChIP-seq in AC16 cell: A Conserved Chromatin Structural Program Underlies Injury-Induced Cardiomyocyte Proliferation

ABSTRACT: Because adult mammalian cardiomyocytes cannot reactivate their proliferative machinery, the heart does not recover effectively after injury. In contrast, during the early neonatal period, cardiomyocytes retain a transient regenerative capacity. Myocardial injury performed before postnatal day 3 triggers robust cardiomyocyte proliferation and complete recovery within weeks, and apical resection during the first postnatal days leads to full regeneration without scar formation. In pigs, apical resection at day 1 followed by myocardial infarction at day 28 induces strong cardiomyocyte proliferation and complete functional recovery by day 56. To investigate the molecular programs that underlie this transient regenerative competence, we reanalyzed mouse and pig snRNA-seq datasets using a cell cycle–specific autoencoder (CSA) and a chromatin structural factor–specific autoencoder (CSF). Both frameworks consistently identified a distinct cardiomyocyte population (CM1) enriched for mitotic markers after injury. Gene Ontology analysis revealed coordinated activation of cell-cycle pathways together with chromatin organization and remodeling processes, suggesting that cell-cycle re-entry requires extensive epigenetic restructuring. Cross-species comparison identified a hallmark of chromatin structural regulators associated to cardiomytocyte proliferation. Among these factors, CTCF emerged as a central regulator. Its expression declined after birth but was robustly reactivated in injured mouse and pig hearts. Functional assays demonstrated that CTCF overexpression promotes cardiomyocyte-like cell proliferation, and induce targeted redistribution of CTCF binding at key cell-cycle regulatory loci. Together, these findings identify conserved modulation of chromatin structural factors as a key mechanism underlying cardiomyocyte cell-cycle reactivation and position CTCF as a prominent regulator within this architectural program during cardiac regeneration.

ORGANISM(S): Homo sapiens

PROVIDER: GSE315886 | GEO | 2026/01/12

REPOSITORIES: GEO

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Project description:Background: Improving heart regeneration through reactivating cardiomyocyte proliferation holds a great potential for repairing diseased hearts. We recently reported that LSD1-dependent epigenetic repression of Cend1 transcription is prerequisite for cardiomyocyte proliferation and mouse heart development. This study interrogates the potential role of this LSD1-CEND1 axis in heart regeneration and repair. Methods: The cardiomyocyte-specific Lsd1 knockout or overexpression mice, Cend1null mice and cardiomyocyte-specific Cend1 overexpression mice were used to determine the role of LSD1-CEND1 axis in heart regeneration after experimental injuries. Neonatal and adult mice were subjected to apical resection or left anterior descending coronary artery ligation, respectively, to establish cardiac injury models. Echocardiography and Masson staining were employed to assess cardiac function and histopathology, respectively. The molecular changes were determined using RNA sequencing, quantitative RT-PCR, Western blotting and immunostaining. Results: Cardiomyocyte-specific deletion impeded neonatal heart regeneration, while overexpression of Lsd1 had the opposite effect. RNA sequencing revealed that Cend1, a crucial suppressor of cardiomyocyte cycling, was the most significantly elevated gene induced by Lsd1 loss during heart regeneration. Cardiomyocyte-specific Cend1 overexpression hindered neonatal heart regeneration, while Cend1 loss in nullizygous mice had the opposite effect. Cend1 deletion resulted in gene expression alterations associated with enhanced cardiomyocyte proliferation, neovascularization, and macrophage activation. Furthermore, the cardiac regeneration defect caused by Lsd1 loss was not observed when experiments were performed with mice that were nullizyogus for Cend1. Moreover, we found that either Lsd1 overexpression or Cend1 deletion could promote heart regeneration and repair, and improve cardiac function following experimental myocardial infraction in adult mice.

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CTCF ChIP-seq in AC16 cell: A Conserved Chromatin Structural Program Underlies Injury-Induced Cardiomyocyte Proliferation

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